Although neutralizing antibodies are likely to be required for an effective AIDS vaccine, to date no candidate vaccine has been found to elicit broad neutralizing responses. A significant fraction of HIV-1-infected individuals eventually develop potent and broad neutralizing antibody responses, typically within 2 to 3 years following infection. The over-arching goal of this Program is to undertake a comprehensive, multidisciplinary effort to define correlates and mechanisms of the development of broadly neutralizing antibody responses. We have assembled an accomplished team of investigators with different fields of expertise and have secured access to two large and well-characterized longitudinal cohorts of primary infection: lAVI Protocol C in sub-Sahara Africa and UCSD First Choice in Southern California that will together provide over 500 eligible participants to be used for the stated goals of the program. We will use a variety of complementary approaches to address fundamental questions concerning the development of broadly neutralizing responses. These questions include: - what are the clinical correlates of the development of broad neutralizing antibody (bNAb) responses? - does the nature of the founder virus influence the development of bNAb responses? - do broad and potent neutralizing responses protect against HIV-1 superinfection? - What are the neutralizing antibody specificities in sera from individuals with broad neutralizing activity? - What is the evolutionary history of bNAb responses? - are there specific viral motifs associated with the development of bNAb responses? - does B cell dysfunction during HIV-infection prevent the development of broad responses? - How do CD4+ T cell helper responses influence the development of the bNAb responses? Answers to these questions will shed light on how and why neutralization breadth develops in some individuals and may reveal efficient vaccine strategies.